Methamphetamine (MA) dependence is associated with long-term damage to regions of the brain that control cognitive and psychiatric function. One-third to one-half of MA dependent adults experience persistent cognitive and other psychiatric disorders up to three years or longer into remission. The neuropsychiatric impairments that persist following abstinence are associated with poorer treatment outcomes (increased relapse and lower treatment retention rates). Emerging evidence demonstrates how immune factors can influence addictive behaviors and contribute to relapse. Our lead compound, recombinant T-cell receptor ligand (RTL)1000 [a partial major histocompatibility complex (pMHC) class II construct with a tethered myelin peptide (pDR2/hMOG-35-55)], addresses the long-term neuroimmune effects of MA addiction and offers a new strategy to treat the persistent MA induced neuronal damage and neuropsychiatric impairments which contribute to relapse. RTLs bind to and downregulate expression of the invariant chain CD74, the primary receptor for macrophage migration inhibitory factor and a key inflammatory mediator in a number of diseases, including alcoholism and MA dependence. The proposed application builds on our previous research by using complimentary human, rodent, and cross-species experiments that will allow us to rapidly move RTL1000 along the drug development pipeline toward readiness for clinical translation. The primary objective of this Phase I STTR project is to evaluate RTL1000 as a medication for MA dependence and test whether RTL1000 can promote abstinent-like behavior and reduce relapse using two different animal models. Secondary objectives will: i) characterize the effects of RTL1000 immunotherapy on the CD74/NF-?B inflammatory signaling cascade, and ii) determine CD74 expression and response to RTL1000 in monocytes from adults with and without a history of MA dependence. Collectively, these secondary objective will: i) establish the degree to which specific inflammatory signals contribute to MA intake and relapse behaviors, and ii) determine the feasibility of using CD74 as a future biomarker for assessing RTL1000 immunotherapy treatment response in patients with MA dependence. We expect that following the completion of this one-year project, we will have substantial evidence to support a new treatment strategy for MA addiction--a strategy which addresses problems that are central to the underlying pathophysiology of MA addiction.